1. Field of the Invention
The invention pertains to the field of pharmaceutical chemistry and provides a process for preparing 2,2-difluoroketene silyl O,S-acetal and .alpha.,.alpha.-difluoro-.beta.-silyloxy-1,3-dioxolane-4-propanoic acid O,S-ester from same.
2. State of the Art
Ketene silyl acetals were first prepared by Petrov, et al.; see J. Gen. Chem. (USSR), 29, 2896-99 (1959). Almost thirty years later, H. Greuter, et al. in Tetrahedron Lett., 29 (27), 3291-94 (1988) taught the use of allylic esters of chlorodifluoroacetic acid in silicon induced Reformatsky-Claisen reactions where 2,2-difluoroketene silyl acetals were inferred to be intermediates. Kobayashi, et al. in Japanese Patent 0,267,250 and Tetrahedron Lett., 29 (15), 1803-06 (1988) described the preparation of 2,2-difluoro ketene silyl acetals by reacting methyl iododifluoro acetate with zinc dust in acetonitrile and treating of the resultant organozinc species (a Reformatsky reagent) with trialkylsilyl chloride. The authors also disclosed the preparation of 2,2-difluoro-2,2-dimethyl-.beta.-(trialkylsilyl)oxy]-1,3-dioxolane-4-propa noic acid methyl esters by reacting 2,3-O-isopropylidene-D-gtyceraldehyde with difluoro ketene silyl acetals generated in situ. It was discovered that difluoro ketene silyl acetals afforded a much higher erythro/threo (anti/syn) ratio than Reformatsky reagents condensed with 2,3-O-isopropylidene glyceraldehydes. Matsumura, et al. in Japanese Patent 2,270,841, described the preparation of anti-.alpha., .alpha.-difluoro-2,2-dimethyl-.beta.-[(trialkylsilyl)oxy]-1,3-dioxolane-4- propanoic acid methyl esters which called for reacting methyl iododifluoro acetate with trialkyl silyl chloride and zinc, in acetonitrile, and treating the resulting mixture with 2,3-O-isopropylidene-D-glyceraldehyde and titanocene dichloride. J. C. Easdon in New Synthetic Methodology for Organofluorine Compounds, Ph.D. Thesis, Chemistry Department, Graduate College of the University of Iowa, July 1987, attempted to make 2,2-difluoroketene silyl acetals by reacting a difluoro acetate ester with lithium hexamethylsilazide and trimethylchlorosilane in tetrahydrofuran at -78.degree. C. R. W. Lang, et al., Tetrahedron Lett., 29 (24), 2943-6 (1988) reported that esters of chlorodifluoroacetic acid undergo Reformatsky-type condensation reactions with aldehydes if treated with activated zinc dust in dimethylformamide. However, lower yields were obtained when aliphatic, enolizable aldehydes, were condensed with chlorodifluoro acetate under similar conditions, unless ultrasonication was used. S. Mcharek, et al., J. Organometallic Chem., 401, 211-15 (1991) reported Reformatsky-type condensation reactions requiring the use of methyl chlorodifluoroacetate and simple aliphatic aldehydes in dimethylformamide, or mixtures of methylene chloride and dimethylformamide, and electrolytic reduction (zinc anode and nickel catalyst). .alpha.,.alpha.-Difluoro-.beta.-silyloxy-1,3-dioxolane-4-propanoic acid esters such as .alpha.,.alpha.-difluoro-2,2-dimethyl-.beta.-[(trialkylsilyl)oxy]-1,3-diox olane-4-propanoic acid methyl ester are used as intermediates in the preparation of antitumor and antiviral nucleoside agents; see for example U.S. Pat. No. 4,526,988.
An object of the present invention is to provide a process for preparing a 2,2-difluoroketene silyl O,S-acetals from chlorodifluoro thioacetates and difluoro thioacetates.
Another object of the present invention is to provide a process for preparing .alpha.,.alpha.-difluoro-.beta.-silyloxy-1,3-dioxolane-4-propanoic acid O,S-esters from 2,2-difluoroketene silyl O,S-acetals.
Other objects and advantages of the present invention will become apparent from the following description and the embodiments contained therein.